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Keywords:

  • regional brain volume;
  • magnetic resonance imaging;
  • adjuvant chemotherapy;
  • breast cancer;
  • voxel-based morphometry

Abstract

  1. Top of page
  2. Abstract
  3. MATERIALS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. Acknowledgements
  7. REFERENCES

BACKGROUND.

Previous studies have shown cognitive impairment in breast cancer survivors who were exposed to adjuvant chemotherapy. Neural damage by chemotherapy might have played some part in these findings. The current study explored the regional brain volume difference between breast cancer survivors exposed to adjuvant chemotherapy (C+) and those unexposed (C−).

METHODS.

High-resolution 1.5-tesla brain magnetic resonance imaging (MRI) databases of breast cancer survivors and healthy controls were used. Brain images were preprocessed for optimal voxel-based morphometry. Comparisons of gray matter and white matter were performed between the C+ and the C− groups, by using MRI scans from within 1 year (the 1-year study, n = 51 and n = 55, respectively) or 3 years after their cancer surgery (the 3-year study, n = 73 and n = 59, respectively). As exploratory analyses, correlation analyses were performed between indices of the Wechsler Memory Scale-Revised and regional brain volume where the volume were significantly smaller. As a reference, MRI scans of cancer survivors were compared with those of healthy controls (n = 55 for the 1-year study and n = 37 for the 3-year study).

RESULTS.

The C+ patients had smaller gray matter and white matter including prefrontal, parahippocampal, and cingulate gyrus, and precuneus in the 1-year study. However, no difference was observed in the 3-year study. The volumes of the prefrontal, parahippocampal gyrus, and precuneus were significantly correlated with indices of attention/concentration and/or visual memory. Comparisons with healthy controls did not show any significant differences.

CONCLUSIONS.

Adjuvant chemotherapy might have an influence on brain structure, which may account for previously observed cognitive impairments. Cancer 2007. © 2006 American Cancer Society.

The survival rate of breast cancer patients is increasing with the development of systemic chemotherapy. In this situation, management of long-term side effects of potentially curative breast cancer treatment is of substantial importance to optimal quality of life of breast cancer survivors. Recently, impairments of cognitive function, which is a prerequisite for functioning in daily life, have been recognized as a possible long-term adverse effect, which has been termed “chemobrain”.1, 2 Previous reviews have shown that most of these studies have consistently indicated impairments of various cognitive domains in breast cancer survivors exposed to adjuvant chemotherapy.3–6 However, the neural mechanisms have not been fully studied.

Neural impairments caused by chemotherapeutic agents as shown in animals may play a part in these mechanisms. Although chemotherapeutic agents were thought initially to have little ability to penetrate the blood-brain barrier, recent studies have indicated higher concentrations than were expected in cerebrospinal fluid and brain tissue.7–9 Chemotherapeutic agents are hypothesized to have neurotoxic potential through their ability to interfere with DNA and RNA synthesis and function, inhibition of microtubule formation, and/or immunosuppressive properties.10, 11 In animals, intracerebroventricularly injected methotrexate was reported to cause learning and memory impairments and damage to the hippocampal CA4 region.12 Injection of doxorubicin into the caudate-putamen indicated neuronal death in the ventral tegmentum and thalamus.13 Intraperitoneal injection of cyclophosphamide produced lesions within the cortex, thalamus, hippocampal dentate gyrus, and caudate nucleus in a dose-dependent fashion.14 In the same report, cyclophosphamide and methotrexate showed a concentration-dependent neurotoxic effect on neuronal cell cultures. Another study has demonstrated that free radicals are a possible mechanism for the toxic effect of chemotherapeutic agents.15

Recently, neuroimaging techniques have developed dramatically, thus enabling investigation of brain structure in humans. In a preliminary investigation that used structural magnetic resonance imaging (MRI), Saykin et al. reported regional brain volumes in breast and lymphoma cancer survivors who lived more than 5 years after their initial treatment.10 Results suggest that chemotherapy may be associated with reductions in regional brain volume. However, a further study is needed with a comparison group of cancer patients unexposed to chemotherapy to control for the impact of cancer diagnosis. Contrary to results of the Saykin et al. investigation, our study showed no significant difference in regional and whole-brain volumes between breast cancer survivors exposed to adjuvant chemotherapy and those unexposed 3 years after their breast cancer surgery.16 Although a previous study indicated long-term cognitive impairment,17 by taking previous reports that show recovery of cognitive impairments over time into consideration,4, 18–20 adverse changes in the brain structure may recover.

In the current study, we explore the regional brain volume difference between cancer survivors exposed to adjuvant chemotherapy and those unexposed in a 2-study setting (the 1-year study of <1 year after surgery and the 3-year study of >3 years after surgery). Our hypothesis was that smaller regional brain volumes would be associated with adjuvant chemotherapy. For secondary analysis, associations were examined between memory functions (as 1 of the cognitive functions) and the regional brain volume, where the volumes are significantly smaller in cancer survivors exposed to adjuvant chemotherapy.

MATERIALS AND METHODS

  1. Top of page
  2. Abstract
  3. MATERIALS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. Acknowledgements
  7. REFERENCES

This study was approved by the Institutional Review Board and the Ethics Committee of the National Cancer Center of Japan and was performed after obtaining written informed consent from patients. This study was conducted by using 2 databases of brain MRI scans from breast cancer survivors. One database (Long-Term-Survivors Database) comprised brain MRI scans of patients 3 years after their breast cancer surgery.16 The other database (Follow-up Database) comprised brain MRI scans from 3–15 months after patients' breast cancer surgery and additional scans from 2 years after their first scan.

Subjects and Procedures

The 1-year study used baseline data from the Follow-up Database (Fig. 1). Subjects were recruited during follow-up visits to the Division of Breast Surgery, National Cancer Center Hospital East. We selected all patients who underwent their breast cancer surgery and who survived >3–15 months. The inclusion criteria were 1) female sex to minimize sex-based brain differences and 2) ages between 18 and 55 years. Exclusion criteria were 1) a history of cancer other than breast cancer or double cancer, 2) bilateral breast cancer, 3) clear evidence of residual or recurrent cancer, 4) current chemotherapy or radiation therapy, 5) a history of any neurological disorders, traumatic brain injury, or psychiatric disorders other than affective and anxiety disorders, 6) psychotropic medication taken within 1 month before participation in the study, 7) a history of substance abuse or dependence, 8) a family history of early dementia, 9) any physical symptoms that interfered with daily life, 10) possible dementia defined as a score of <24 on the Mini-Mental State Examination,21, 22 11) a history of major depression and/or post-traumatic stress disorder (PTSD) before inspection for cancer diagnosis to exclude regional brain volume changes brought about by these disorders,23 and 12) any contraindication to undergoing an MRI scan.

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Figure 1. Subject sampling in the 1-year study and the 3-year study. SCID indicates the Structured Clinical Interview for DSM-IV Axis I Disorder, clinician version; MRI, magnetic resonance imaging; PTSD, post-traumatic stress disorder. In the 1-year study, the age and medical factors significantly differ between the 105 subjects and the 190 patients who did not participate because of our mistake to make contact with patients, patient refusal to participate, or MRI examination error were positive lymph node metastases found in their surgical tissue (31% versus 44%, χ2 = 4.4, P = .04), poor histological grade (27% versus 56%, χ2 = 21.1, P<.01), and receiving adjuvant chemotherapy (49% versus 62%, χ2 = 5.1, P = .02), respectively. In the 3-year study, age and medical factors that differed significantly between 132 subjects who participated in the study and 300 cancer survivors who did not participate were age (mean 44 years versus 46 years, t = 3.7, P<.001), presence of positive lymph node metastases (32% versus 43%, χ2 = 4.9, P = .03), poor histological grade (37% versus 49%, χ2 = 4.9, P = .03), and receiving hormonal therapy (35% versus 23%, χ2 = 7.0, P = .01), respectively.

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For the 3-year study, subjects were collected from the Follow-Up Database and the Long-Term-Survivor Database. From the Follow-Up Database, 105 subjects who participated in the 1-year study were asked to participate in the follow-up more than 2 years after their 1-year study.16 Figure 1 indicates a summary of the recruitment of participants to the 1-year study and to the 3-year study.

We recruited healthy subjects, who lived in the same geographic areas as the patients, by using advertisements in the local newspaper. The inclusion and exclusion criteria were the same as those for cancer patients except for the requirement of a history of breast cancer surgery. Fifty-five healthy controls participated in the 1-year study. After 2 years, 37 of 55 healthy controls participated again in the 3-year study.

Neuropsychological Measurements

The Wechsler Memory Scale-Revised Japanese version was performed. The Wechsler Memory Scale-Revised (WMS-R),24 a memory function scale validated in Japanese,25, 26 consists of indices of Attention/Concentration, Immediate Visual Memory, Immediate Verbal Memory, and Delayed Recall to estimate memory function. This scale is among the most generalized and widely used in the world.

Image Data Processing for Optimized Voxel-based Morphometry

MRI scans were conducted on a 1.5-tesla MRI unit (Signa Scanner, GE Medical Systems, Milwaukee, Wis), with 3-dimensional, spoiled gradient-recalled acquisition of 1.5-mm contiguous sections under the following conditions: field of view = 230 mm, matrix = 256 × 256 pixels, repetition time = 25 milliseconds, echo time = 5 milliseconds, and flip angle = 45°.16

The theory and algorithm of voxel-based morphometry (VBM) for Statistical Parametric Mapping 2 (SPM2) software (Wellcome Department of Cognitive Neurology, London, UK) have been well documented.27 VBM was carried out by using an optimized method.28 First, optimized study-specific template sets for the 1-year study and for the 3-year study comprising a T1 image and a priori gray matter, white matter, and cerebrospinal fluid images were created on the basis of brain images of participants in the 1-year study and the 3-year study, respectively. All scans were spatially normalized to customized templates, and then they were smoothed with an 8-mm, full-width half-maximum (FWHM) smoothing kernel, followed by averaging to create customized templates. Next, for the study group MRI scans, a brain extraction procedure that incorporated a segmentation step was used to remove nonbrain tissue from the MRI images.28, 29 Extracted gray matter and white matter images were normalized to the gray matter and white matter templates.27, 30 The normalization parameters were then reapplied to the original structural images to maximize optimal segmentation of fully normalized images, and these normalized images were segmented into gray matter/white matter and cerebrospinal fluid/noncerebrospinal fluid partitions.31 Segmented images were modulated by the Jacobian determinants from spatial normalization to correct for volume changes that were introduced during nonlinear spatial transformations.28 Finally, images were smoothed with a 12-mm FWHM kernel.27, 32

Statistical Analysis

Student t test, Mann-Whitney U test, or χ2 tests were used for comparison of background and medical factors. α levels were set at P < .05 (2-tailed).

By using SPM2, group differences in each of the gray matter and white matter scans were compared between the cancer patients exposed to their adjuvant chemotherapy and those unexposed, by using ANCOVA models, respectively, with age, alcohol consumption, intracranial volume, and background characteristics significantly different between these 2 groups (in the 1-year study, number of days after surgery and current hormonal therapy; in the 3-year study, handedness and current hormonal therapy) as nuisance variables. The intracranial volumes (sum of the gray matter, white matter, and cerebrospinal fluid volumes) were calculated from non-normalized segmented images during optimized-VBM preprocessing. Height and weight were not included as nuisance variables because intracranial volumes were modeled. Medical factors that seemed to be causes or results of adjuvant chemotherapy were not included as nuisance variables to avoid overmatching between the 2 groups. The groups were compared using statistical t-test contrasts within SPM2. The distribution of morphological differences across each of the total gray matter or white matter was assessed initially on a voxel-by-voxel basis; clusters of over 400 voxels were used to suppress small clusters possibly arising by chance, and a threshold of P < .001 was used, uncorrected for multiple comparisons. Inference was centered on differences that achieved a significance of P < .05, after family-wise error correction for multiple comparisons.33 In all analyses, we reported the Montreal Neurological Institute (MNI) coordinates of voxels of statistical significance.34

To see the effect of cancer on the brain structure as a reference, MRI scans of cancer survivors were compared with those of healthy controls, by using ANCOVA models with age, alcohol consumption, intracranial volume, and background characteristics significantly different between these 2 groups (in the 1-year study, year of education and menopausal state; in the 3-year study, no additional covariate) as nuisance variables.

For subanalyses, we examined the correlations between indices of the WMS-R and regional brain volume of the voxel where cancer survivors exposed to adjuvant chemotherapy had a significantly smaller brain region. Regional brain volumes of the voxels were calculated by using the region of interest (ROI) function in the SPM2 software as a substitution for the regional brain volume index.

RESULTS

  1. Top of page
  2. Abstract
  3. MATERIALS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. Acknowledgements
  7. REFERENCES

Table 1 shows the background and medical factors of each group in both the 1-year study and the 3-year study. Eight percent of the survivors in the 1-year study and 8% of those in the 3-year study received tegafur and uracil (UFT) for <80 days. Ten percent of survivors in the 1-year study and 7% in the 3-year study received 5 of 6 cycles of their cyclophosphamide, methotrexate, and 5-fluorouracil regimen, and others completed their regimen in the 1-year study and in the 3-year study, respectively. In other cases, quantities of each of the administered chemotherapeutic agents complied with the protocols of each regimen.

Table 1. Demographic Information of Cancer Patients With and Without Adjuvant Chemotherapy, and Healthy Control Samples in the 1-Year and 3-Year Studies
CharacteristicsSample 1 (1-Year study)Sample 2 (3-Year study)
Patients Patients 
Adjuvant chemotherapy +Adjuvant chemotherapy −Healthy controlsAdjuvant chemotherapy +Adjuvant chemotherapy −Healthy controls
(n = 51)(n = 54)(n = 55)(n = 73)(n = 59)(n = 37)
  • NA indicates not applicable; PTSD, post-traumatic stress disorder; AC, regimen with doxorubicin and cyclophosphamide; CMF, regimen with cyclophosphamide, methotrexate and fluorouracil; EC, regimen with epirubicin and cyclophosphamide; PTX, paclitaxel; 5-FU, fluorouracil; 5′-DFUR, doxifluridine; HCFU, carmofur; UFT, tegafur/uracil; WMS-R, the Wechsler Memory Scale-Revised.

  • *

    Indicates significant difference (P < .05) between adjuvant chemotherapy group and no-adjuvant chemotherapy group.

  • indicates significant difference (P < .01) between adjuvant chemotherapy group and no-adjuvant chemotherapy group.

  • §

    Indicates significant difference (P < .01) between cancer patients group and healthy control group.

Age, mean ± SD, y47.3 ± 5.246.3 ± 6.146.2 ± 6.748.2 ± 5.648.4 ± 4.848.0 ± 6.4
Handedness: right-handedness, no. (%)51 (100)51 (94.4)51 (92.7)73 (100)55 (93.2)*33 (89.2)
Height, mean ± SD, cm155.0 ± 5.6157.9 ± 5.8*157.2 ± 5.0156.4 ± 5.6157.5 ± 6.0156.6 ± 5.2
Weight, mean ± SD, kg54.8 ± 6.656.9 ± 8.654.1 ± 7.955.1 ± 6.558.2 ± 8.7*53.9 ± 8.0§
Education, mean ± SD, y13.2 ± 1.713.2 ± 2.014.1 ± 1.9§12.8 ± 1.713.2 ± 2.014.1 ± 1.7
Smoking, no. (%)5 (9.8)6 (11.1)2 (3.6)12 (16.4)7 (11.9)2 (5.4)
Accumulated alcohol consumption, mean ± SD, g × 10327 ± 8739 ± 5929 ± 5916 ± 4247 ± 7538 ± 66
Postmenopausal, no. (%)40 (78.4)20 (37.0)16 (29.1)§47 (64.4)19 (32.2)15 (40.5)
Performance status: 0, no. (%)30 (60.0)43 (81.1)*36 (97.3)§67 (94.4)57 (98.3)35 (97.2)
Clinical stage: 0–I, no. (%)14 (27.5)25 (46.3)*NA14 (19.2)30 (50.8)NA
Lymphnode metastasis, positive, no. (%)29 (56.9)4 (7.4)NA41 (56.2)1 (1.7)NA
Histological type, no. (%)
 Carcinoma in situ2 (3.9)4 (7.4)NA1 (1.4)4 (6.8)NA
 Invasive carcinoma42 (82.4)41 (75.9)NA61 (83.6)49 (83.1)NA
 Special type7 (13.7)9 (16.7)NA11 (15.1)6 (10.2)NA
Histological grade: poor, no. (%)21 (41.2)7 (13.0)NA36 (49.3)13 (22.0)NA
Surgical type: partial mastectomy, no. (%)25 (49.0)32 (59.3)NA27 (37.0)30 (50.8)NA
Axillary lymphadectomy, no. (%)42 (82.4)28 (51.9)NA68 (93.2)43 (72.9)NA
Days after surgery, mean ± SD, d345 ± 71234 ± 103NA1641 ± 3601416 ± 316NA
Protocol of adjuvant chemotherapy, no. (%)
 AC3 (5.9)NANA15 (20.5)NANA
 CMF40 (78.4)NANA37 (50.7)NANA
 EC2 (3.9)NANA1 (1.4)NANA
 PTX2 (3.9)NANA1 (1.4)NANA
 5-FU0 (0)NANA9 (12.3)NANA
 5′-DFUR0 (0)NANA1 (1.4)NANA
 HCFU0 (0)NANA2 (2.7)NANA
 UFT5 (9.8)NANA7 (9.6)NANA
Days after adjuvant chemotherapy, mean ± SD, d119 ± 47NANA1189 ± 359NANA
Hormonal therapy20 (39.2)11 (20.4)*NA21 (28.8)5 (8.5)NA
Radiation therapy, no. (%)25 (49.0)26 (48.1)NA23 (31.5)19 (32.2)NA
WMS-R index, mean ± SD
 Attention99.4 ± 12.599.5 ± 11.599.6 ± 13.098.6 ± 10.4103.0 ± 11.1*NA
 Verbal memory96.9 ± 13.0101.7 ± 14.599.2 ± 14.4100.4 ± 15.6103.3 ± 14.7NA
 Visual memory101.9 ± 12.1102.7 ± 11.4101.4 ± 10.3103.7 ± 10.4104.1 ± 12.7NA
 Delayed recall100.3 ± 10.4102.5 ± 12.2100.7 ± 12.6103.9 ± 12.6105.5 ± 11.5NA
History of major depression, No. (%)6 (11.8)2 (3.7)NA20 (27.4)8 (13.6)0 (0)
History of PTSD, No. (%)5 (9.8)4 (7.4)NA5 (6.8)2 (3.4)0 (0)

The peak voxel coordinates of the smaller regions in cancer survivors exposed to adjuvant chemotherapy compared with those unexposed using corrected P < .05 are presented in Table 2. Figures 2 and 3 indicate superimposed images of the statistical t map (regional brain volume in cancer survivors exposed to adjuvant chemotherapy less than regional brain volume in those unexposed) on the template T1 image in the 1-year study. There was no significantly bigger region in cancer survivors exposed to adjuvant chemotherapy in the 1-year study. As an ad hoc analysis, we performed comparisons of gray matter and white matter between cancer survivors exposed to a cyclophosphamide, methotrexate, and 5-fluorouracil regimen (n = 40) and those unexposed to any adjuvant chemotherapy (n = 54). The distributions of regional brain volume difference were similar to those observed in the primary comparisons in the 1-year study (data not shown). There were no significantly smaller regions in gray matter and white matter when we used a corrected P < .05 in cancer survivors exposed to adjuvant chemotherapy in the 3-year study, as shown in Table 2.

thumbnail image

Figure 2. The superimposition of the t-value map of smaller gray matter in cancer survivors exposed to their adjuvant chemotherapy compared with those unexposed onto coronal slices of the customized T1 template image in the 1-year study. The color bar indicates the t value.

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thumbnail image

Figure 3. The superimposition of the t-value map of smaller white matter in cancer survivors exposed to their adjuvant chemotherapy compared with those unexposed onto coronal slices of the customized T1 template image in the 1-year study. The color bar indicates the t value.

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Table 2. Regions of Smaller Gray Matter and Nearest Gray Matter to Smaller White Matter in Breast Cancer Survivors With Adjuvant Chemotherapy Compared With Those Without Adjuvant Chemotherapy
1-year study (3 to 15 months after breast cancer surgery)
 Coordinates of peak differenceSidet score*Corrected PRegion
xyz
  • *

    All scores significant (P < .05) after family-wise error correction for multiple comparisons over each area of gray or white matter.

  • Gray matter or nearest gray matter regions were indicated.

Gray matter30668Right4.77.031Middle frontal gyrus
10714Right4.73.035Superior frontal gyrus
1365−12Right4.66.045Superior frontal gyrus
21−40−11Right4.63.048Parahippocampal gyrus
White matter−11−6064Left5.38.005Precuneus
354330Right5.12.013Middle frontal gyrus
−13−33−5Left4.97.023Parahippocampal gyrus
1049−1Right4.95.025Cingulate gyrus
−104944Left4.93.026Middle frontal gyrus
3-year study (27 to 39 months after breast cancer surgery)
Gray matterNone
White matterNone

In referential analyses, there were no significantly smaller or bigger regions in gray matter and white matter between cancer survivors and healthy controls in the 1-year study and in the 3-year study.

Table 3 indicates that significant correlations between memory functions and regional brain volumes at the coordinates are significantly smaller in cancer survivors exposed to adjuvant chemotherapy in the 1-year study.

Table 3. Correlations Between Memory Functions and the Regional Brain Volume in the 1-Year Study
 x-y-z coordinate (Region)
Gray matter regionsWhite matter regions
30 66 810 71 413 65 −1221 −40 1111 60 6435 43 3013 33 −510 49−1−10 49 44
(mFG)(sFG)(sFG)(pHG)(Pc)(mFG)(pHG)(CG)(mFG)
  • WMS-R indicates the Wechsler Memory Scale-Revised; mFG, middle frontal gyrus; sFG, superior frontal gyrus; pHG, parahippocampal gyrus; Pc, precuneus; CG, cingulate gyrus.

  • Data indicate r value of the Pearson correlation test.

  • *

    Indicates significant association (P < .05).

WMS-R index
 Attention/concentration0.150.25*0.080.120.21*−0.030.060.090.12
 Visual memory0.100.24*0.120.20*0.13−0.020.110.040.08
 Verbal memory−0.010.110.090.060.160.050.030.020.01
 Delayed recall−0.030.09−0.01−0.010.13−0.02−0.02−0.08−0.08

DISCUSSION

  1. Top of page
  2. Abstract
  3. MATERIALS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. Acknowledgements
  7. REFERENCES

The current study showed smaller right prefrontal and parahippocampal gyrus in cancer survivors who were exposed to adjuvant chemotherapy before the mean of 4 months, compared with those unexposed. These volume differences were not found in cancer survivors at a mean of 4.2 years after completion of their adjuvant chemotherapy. In subanalyses, the volumes of the right superior frontal gyearus, 1 of the smaller regions in cancer survivors exposed to adjuvant chemotherapy, were associated with memory functions. These results indicate a potential effect of adjuvant chemotherapy on brain structure, and the change of the brain structure may be associated with memory function.

A previous report using VBM in 10 breast cancer and 2 lymphoma survivors (>5 years) exposed to chemotherapy showed smaller regional gray matter and cortical and subcortical white matter brain regions compared with healthy controls.10 Chemotherapeutic agents included in the previous report were similar to those in the current study. Contrary to results of the previous report, the results of the current study did not show any significant difference in regional brain volume as shown in the 3-year study. These findings were consistent with our previous study where we used a manual tracing method, which is a different method from the VBM, to measure regional brain volume.16 That study indicated that there were no significantly smaller hippocampal and amygdalar volumes among breast cancer survivors who had survived >3 years since their surgery. This difference in results may be caused by differences in the methods, such as number and characteristics of subjects, comparisons with cancer survivors unexposed to chemotherapy, and/or use of corrections for multiple comparisons, as in the current study.

The current study indicated regional brain volume differences in the superior and middle frontal gyri, parahippocampal gyrus, cingulate gyrus, and precuneus. The significantly smaller volume of the superior frontal gyrus in the current study was correlated with the attention/concentration and visual memory indices of the WMS-R. The prefrontal cortex, including superior and middle frontal gyri, has been reported to have roles in various functions including memory, planning, execution, monitoring of cognitive processing and behavior, and inhibition and change in circumstantial behavior.35 Not all, but many, of the studies in cancer survivors exposed to adjuvant chemotherapy have reported impairments in various cognitive domains including attention/concentration and visual memory functions.3–6 The structural differences of the superior and middle prefrontal gyrus may partly account for some of the previously reported cognitive impairments and complaints referred to as “chemobrain”. A previous positron emission tomography study of breast cancer survivors in whom the researchers had found significant neurocognitive changes associated with adjuvant chemotherapy, including impairment of verbal learning, demonstrated hypometabolism in the superior frontal gyearus. In addition to the prefrontal cortex, the parahippocampal gyrus is associated with cognitive functions, such as memory function.36 Recently, the precuneus was also thought to have important roles in self-centered mental imagery strategies and episodic memory retrieval,37 and these concepts lead us to suppose the potential engagement of structural changes in these brain regions in cognitive impairments caused by adjuvant chemotherapy.

The distribution of the regional brain volume differences observed in the 1-year study did not reappear in the 3-year study. Results from the 1-year and 3-year studies can lead us to speculate that the brain volume change related to adjuvant chemotherapy may well recover over the course of time. Although a previous report showed cognitive impairments in cancer survivors even after a long period following completion of adjuvant chemotherapy,17 several longitudinal studies18–20 and a review article4 have demonstrated recovery from cognitive impairment in breast cancer survivors exposed to adjuvant chemotherapy. Regional brain structural changes and cognitive impairments observed in cancer survivors exposed to adjuvant chemotherapy may recover in time.

In reference comparisons between cancer survivors and healthy controls both in the 1-year study and in the 3-year study, there were no significant differences in regional brain volume. These results support the idea that cancer had little influence on the main analyses of the current study. We did not include healthy controls in the primary comparisons. We did not make a model, such as a 2-factorial ANCOVA in which 1 factor is cancer survivors versus healthy controls and the other factor is whether chemotherapy was received or not, because of the lack of any healthy controls exposed to adjuvant chemotherapy.

The current study has several limitations. 1) Background and medical factors were entered into statistical models as nuisance variables, and medical factors usually used to judge the application of adjuvant chemotherapy and factors reported as a result of adjuvant chemotherapy were not entered to avoid overadjustment. Given potential biases, results need to be interpreted with caution. 2) Effects of each regimen or each chemotherapeutic agent on regional brain volumes were unclear. 3) Pathophysiological mechanisms of volume differences were unclear. The other reason we did not explore effects of each chemotherapeutic agent in the study setting was that interactions between each chemotherapeutic agent may exist and may make our inference difficult. 4) The VBM has several limitations. A method with higher sensitivity, such as a manual tracing method like those reported previously,16 should be used. 5) The current study did not have any specific functional targets related to each of the detected regions. Functions related to brain regions significantly different in volume from those in the current study need to be examined by using specific neuropsychological tasks and neuroimaging of brain function.

In conclusion, the current study showed significantly smaller regional brain volumes in areas related to cognitive functions in cancer survivors who received adjuvant chemotherapy. The smaller regional brain volumes were not observed at more than 3 years after completion of adjuvant chemotherapy. Results lead to the idea that adjuvant chemotherapy could have a temporary effect on brain structure. These findings can provide new insights for future research to improve the quality of life of cancer patients who receive adjuvant chemotherapy.

Acknowledgements

  1. Top of page
  2. Abstract
  3. MATERIALS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. Acknowledgements
  7. REFERENCES

Supported in part by a third-term comprehensive control research for cancer fund from the Japanese Ministry of Health, Labor, and Welfare; supported in part by a grant from the Japan Society for the Promotion of Science; and supported in part by a grant from the Japanese Ministry of Education, Culture, Science, and Technology. The funding sources had no involvement in study design, data collection, data analyses, or data interpretations, or in writing the report, or in the decision to submit the current study for publication.

We thank Ms. Nobue Taguchi, Yuko Kojima, Yukiko Kozaki, and Ryoko Katayama for their research assistance.

REFERENCES

  1. Top of page
  2. Abstract
  3. MATERIALS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. Acknowledgements
  7. REFERENCES
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